Pulmonary lesion after surgery for renal cancer: progression or new primary?

PURPOSE: To investigate clinical and radiological differences between kidney metastases to the lung (RCCM +) and metachronous lung cancer (LC) detected during follow-up in patients surgically treated for Renal Cell Carcinoma (RCC). METHODS: cM0 surgically-treated RCC who harbored a pulmonary mass during follow-up were retrospectively scrutinized. Univariate logistic regression assessed predictive features for differentiating between LC and RCCM + . Multivariable analyses (MVA) were fitted to predict factors that could influence time between detection and histological diagnosis of the pulmonary mass, and how this interval could impact on survivals. RESULTS: 87% had RCCM + and 13% had LC. LC were more likely to have smoking history (75% vs. 29%, p < 0.001) and less aggressive RCC features (cT1-2: 94% vs. 65%, p = 0.01; pT1-2: 88% vs. 41%, p = 0.02; G1-2: 88% vs. 37%, p < 0.001). The median interval between RCC surgery and lung mass detection was longer between LC (55 months [32.8-107.2] vs. 20 months [9.0-45.0], p = 0.01). RCCM + had a higher likelihood of multiple (3[1-4] vs. 1[1-1], p < 0.001) and bilateral (51% vs. 6%, p = 0.002) pulmonary nodules, whereas LC usually presented with a solitary pulmonary nodule, less than 20 mm. Univariate analyses revealed that smoking history (OR:0.79; 95% CI 0.70-0.89; p < 0.001) and interval between RCC surgery and lung mass detection (OR:0.99; 95% CI 0.97-1.00; p = 0.002) predicted a higher risk of LC. Conversely, size (OR:1.02; 95% CI 1.01-1.04; p = 0.003), clinical stage (OR:1.14; 95% CI 1.06-1.23; p < 0.001), pathological stage (OR:1.14; 95% CI 1.07-1.22; p < 0.001), grade (OR:1.15; 95% CI 1.07-1.23; p < 0.001), presence of necrosis (OR:1.17; 95% CI 1.04-1.32; p = 0.01), and lymphovascular invasion (OR:1.18; 95% CI 1.01-1.37; p = 0.03) of primary RCC predicted a higher risk of RCCM + . Furthermore, number (OR:1.08; 95% CI 1.04-1.12; p < 0.001) and bilaterality (OR:1.23; 95% CI 1.09-1.38; p < 0.001) of pulmonary lesions predicted a higher risk of RCCM + . Survival analysis showed a median second PFS of 10.9 years (95% CI 3.3-not reached) for LC and a 3.8 years (95% CI 3.2-8.4) for RCCM + . The median OS time was 6.5 years (95% CI 4.4-not reached) for LC and 6 years (95% CI 4.3-11.6) for RCCM + . CONCLUSIONS: Smoking history, primary grade and stage of RCC, interval between RCC surgery and lung mass detection, and number of pulmonary lesions appear to be the most valuable predictors for differentiating new primary lung cancer from RCC progression.

Preoperative risk calculator for the probability of completing nephron sparing for kidney cancer.

PURPOSE: In absence of predictive models, preoperative estimation of the probability of completing partial (PN) relative to radical nephrectomy (RN) is invariably inaccurate and subjective. We aimed to develop an evidence-based model to assess objectively the probability of PN completion based on patients' characteristics, tumor's complexity, urologist expertise and surgical approach. DESIGN, SETTING AND PARTICIPANTS: 675 patients treated with PN or RN for cT1-2 cN0 cM0 renal mass by seven surgeons at one single experienced centre from 2000 to 2019. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSES: The outcome of the study was PN completion. We used a multivariable logistic regression (MVA) model to investigate predictors of PN completion. We used SPARE score to assess tumor complexity. We used a bootstrap validation to compute the model's predictive accuracy. We investigated the relationship between the outcomes and specific predictors of interest such as tumor's complexity, approach and experience. RESULTS: Of 675 patients, 360 (53%) were treated with PN vs. 315 (47%) with RN. Smaller tumors [Odds ratio (OR): 0.52, 95%CI 0.44-0.61; P < 0.001], lower SPARE score (OR: 0.67, 95%CI 0.47-0.94; P = 0.02), more experienced surgeons (OR: 1.01, 95%CI 1.00-1.02; P < 0.01), robotic (OR: 10; P < 0.001) and open (OR: 36; P < 0.001) compared to laparoscopic approach resulted associated with higher probability of PN completion. Predictive accuracy of the model was 0.94 (95% CI 0.93-0.95). CONCLUSIONS: The probability of PN completion can be preoperatively assessed, with optimal accuracy relaying on routinely available clinical information. The proposed model might be useful in preoperative decision-making, patient consensus, or during preoperative counselling. PATIENT SUMMARY: In patients with a renal mass the probability of completing a partial nephrectomy varies considerably and without a predictive model is invariably inaccurate and subjective. In this study we build-up a risk calculator based on easily available preoperative variables that can predict with optimal accuracy the probability of not removing the entire kidney.

Long-term functional outcomes in patients undergoing radical nephrectomy for renal cell carcinoma and tumor thrombus.

BACKGROUND: Up to 15% of patients with locally advanced renal cell carcinoma (RCC) harbors tumor thrombus (TT). In those cases, radical nephrectomy (RN) and thrombectomy represents the standard of care. We assessed the impact of TT on long-term functional and oncological outcomes in a large contemporary cohort. METHODS: Within a prospective maintained database, 1207 patients undergoing RN for non-metastatic RCC between 2000 and 2021 at a single tertiary centre were identified. Of these, 172 (14%) harbored TT. Multivariable logistic regression analyses evaluated the impact of TT on the risk of postoperative acute kidney injury (AKI). Multivariable Poisson regression analyses estimated the risk of long-term chronic kidney disease (CKD). Kaplan Meier plots estimated disease-free survival and cancer specific survival. Multivariable Cox regression models assessed the main predictors of clinical progression (CP) and cancer specific mortality (CSM). RESULTS: Patients with TT showed lower BMI (24 vs. 26 kg/m2) and preoperative Hb (11 vs. 14 g/mL; all-p < 0.05). Clinical tumor size was higher in patients with TT (9.6 vs. 6.5 cm; p < 0.001). After adjusting for potential confounders, the presence of TT was significantly associated with a higher risk of postoperative AKI (OR 2.03, 95% CI 1.49-3.6; p < 0.001) and long-term CKD (OR: 1.32, 95% CI 1.10-1.58; p < 0.01). Notably, patients with TT showed worse long-term oncological outcomes and TT was a predictor for CP (2.02, CI 95% 1.49-2.73, p < 0.001) and CSM (HR 1.61, CI 95% 1.04-2.49, p < 0.03). CONCLUSIONS: The presence of TT in RCC patients represents a key risk factor for worse perioperative, as well as long-term renal function. Specifically, patients with TT harbor a significant and early estimated glomerular filtration rate (eGFR) decrease. However, despite TT patients show a greater eGFR decline after surgery, they retain acceptable renal function, which remains stable over time.

Risks and benefits of partial nephrectomy performed with limited or with zero ischaemia time.

OBJECTIVE: To test the hypothesis that longer warm ischaemia time (WIT) might have a marginal impact on renal functional outcomes and might, in fact, reduce haemorrhagic risk intra-operatively. PATIENTS AND METHODS: Data from 1140 patients treated with elective partial nephrectomy (PN) for a cT1-2 cN0 cM0 renal mass were prospectively collected. WIT was defined as the duration of clamping of the main renal artery with no refrigeration and was tested as a continuous variable. The primary outcome of the study was evaluation of the effect of WIT on renal function (estimated glomerular filtration rate [eGFR]) postoperatively, at 6 months and in the long term (measured between 1 and 5 years after surgery). The secondary outcome of the study was haemorrhagic risk, defined as estimated blood loss (EBL) or peri-operative transfusions. Multivariable linear, logistic and Cox regression analyses, accounting for age, Charlson comorbidity index, clinical size, preoperative eGFR and year of surgery, were used and the potential nonlinear relationship between WIT and the study outcomes was modelled using restricted cubic splines. RESULTS: A total of 863 patients (76%) underwent PN with WIT and 277 (24%) without. The baseline median eGFR was 87.3 (68.8-99.2) mL/min/1.73m2 for the on-clamp population and 80.6 (63.2-95.2) mL/min/1.73m2  for the off-clamp population. The median duration of WIT was 17 (13-21) min. At multivariable analyses predicting renal function, longer WIT was associated with decreased postoperative eGFR (estimate: -0.21, 95% confidence interval [CI] -0.31; -0.11 [P < 0.001]). Conversely, no association between WIT and eGFR was recorded at 6-month or long-term follow-up (all P > 0.8). At multivariable analyses predicting haemorrhagic risk, clampless resection with no ischaemia time and PN with short WIT was associated with an increased EBL (estimate: -21.56, 95% CI -28.33; -14.79 [P < 0.001]) and peri-operative transfusion rate (estimate: -0.009, 95% CI -0.01; -0.003 [P = 0.002]). No association between WIT and positive surgical margin status was recorded (all P = 0.1). CONCLUSION: Patients and clinicians should be aware that performing PN with very limited or even with zero WIT might increase bleeding and the need for peri-operative transfusion while not improving long-term renal function outcomes.

Differential Prognostic Value of Extrarenal Involvement in Patients With Non-Metastatic Renal Cell Cancer.

INTRODUCTION: A better definition of the prognostic significance of non-metastatic pT3a stage RCC subcategories is crucial to select the best candidate for adjuvant treatment. The aim of the study is to investigate the differential prognosis of extrarenal involvement in patients with non-metastatic pT3a RCC. MATERIALSAND METHODS: From a single institutional prospective database, 451 consecutive patients treated for pT3aN0/NxM0 RCC were selected and stratified according to pT3a subtypes (perirenal fat invasion, sinus fat invasion, segmental/renal vein thrombus, ≥ 2 features). Cancer specific survival (CSS), metastasis free survival (MFS) and relapse free survival (RFS) were primary endpoints of multivariable Cox regression models. RESULTS: Overall, 67 (15%) patients presented with renal/segmental vein thrombus only, 185 (41%) with perirenal fat invasion, 101 (22%) with sinus fat invasion and 98 (22%) with ≥ 2 features. The presence of ≥ 2 pT3a features was associated with a higher risk of metastasis (HR=2.36; 95%CI 1.30-4.27; P value = .005), recurrence (HR=2.41; 95%CI 1.36-4.28; P value=.003) and cancer specific mortality (HR=3.54; 95%CI 1.45-8.63; P value = .005) compared to only 1 pT3a feature. Moreover, the presence of perirenal fat invasion was associated with lower CSS (HR=2.82; 95% CI 1.19-6.69; P value = .02) compared to sinus fat invasion or tumoral thrombus only. CONCLUSION: The concurrent presence of ≥ 2 pT3a features is associated to a higher risk of distant progression, relapse and cancer specific mortality, implying potential role for adjuvant therapy or a more stringent follow-up. Moreover, perirenal fat invasion is associated with worse CSS compared to other pT3a patterns taken alone.

How to optimize the use of adjuvant pembrolizumab in renal cell carcinoma: which patients benefit the most?

PURPOSE: The KEYNOTE-564 trial showed improved disease-free survival (DFS) for patients with high-risk renal cell carcinoma (RCC) receiving adjuvant pembrolizumab as compared to placebo. However, if systematically administered to all high-risk patients, it might lead to the overtreatment in a non-negligible proportion of patient. Therefore, we aimed to determine the optimal candidate for adjuvant pembrolizumab. METHODS: Within a prospectively maintained database we selected patients who fulfilled the inclusion criteria of the KEYNOTE-564. We compared baseline characteristics and oncologic outcomes in this cohort with those of the placebo arm of the KEYNOTE-564. Regression tree analyses was used to generate a risk stratification tool to predict 1-year DFS after surgery. RESULTS: In the off-trial setting, patients had worse tumor characteristics then in the KEYNOTE-564 placebo arm, i.e. there were more pT4 (5.4 vs. 2.7%, p = 0.046) and pN1 (15 vs. 6.3%, p < 0.001) cases. Median DFS was 29 (95% CI 21-35) months as compared to value not reached in KEYNOTE-564 and 1-year DFS was 64.2% (95% CI 59.6-69.2) as compared to 76.2% (95% CI 72.2-79.7), respectively. Patients with pN1 were at the highest risk of 1-year recurrence (1-year DFS 28.6% [95% CI 20.2-40.3]); patients without LNI, but necrosis were at intermediate risk (1-year DFS 62.5% [95% CI 56.9-68.8]); those without LNI and necrosis were at the lowest risk (1-year DFS 83.8% [95% CI 79.1-88.9]). LVI substratification furtherly improved the accuracy in the prediction of early recurrence. CONCLUSIONS: Patients potentially eligible for adjuvant pembrolizumab have worse characteristics and DFS in the off-trial setting as compared to the placebo arm of the KEYNOTE-564. Patients with either LNI or necrosis were at the highest risk of early-recurrence, which make them the ideal candidate to adjuvant pembrolizumab.

Head-to-head comparison of all the prognostic models recommended by the European Association of Urology Guidelines to predict oncologic outcomes in patients with renal cell carcinoma.

OBJECTIVES: European Urology Association guidelines suggest the use of integrated prognostic systems to assess oncologic outcomes after surgery in patients with localized renal cell carcinoma (RCC). We performed a head-to-head comparison among all the EAU guidelines recommended prognostic models in RCC. METHODS: The study included 2,014 patients treated with surgery for clinically localized RCC. Patients were classified into prognostic risk groups, based on each of the five EAU guidelines recommended prognostic model definition, namely UISS, Leibovich 2003, VENUSS, GRANT, and Leibovich 2018 score. Prognostic accuracy of each prognostic model to predict clinical progression or cancer-specific mortality (CSM) was assessed, and ROC curves were calculated, according to histological subtype, namely clear-cell, papillary, and chromophobe RCC. RESULTS: Of 2,014 patients, 1,575 (78%) harboured clear-cell, 312 (16%) papillary, and 127 (6%) chromophobe RCC. Median follow-up was 66 months [Interquartile range (IQR): 29-120]. In clear-cell RCC, low-risk patients rates ranged from 21% to 64%, according prognostic model. The same phenomenon was observed for papillary and chromophobe RCC. In clear-cell RCC, Leibovich 2018 resulted the most accurate model in predicting clinical progression (88.1%) and CSM (86.8%). Conversely, VENUSS or UISS prognostic models predicting oncologic outcomes represented the most accurate in papillary (88.7% and 84.8%) or chromophobe (87.8% and 89.1%) RCC, respectively. CONCLUSIONS: A non-negligible difference in terms of performance accuracy exists among the EAU guidelines recommended prognostic models. Thus, their adoption in RCC should be histology-specific and follow-up strategies based on prognostic risk class appear justified only if the appropriate model is used to stratify patients into prognostic risk groups.

Analysis of implantable cardioverter defibrillator signals for non conventional cardiac electrical activity characterization.

Implantable cardioverter defibrillators (ICDs) can store intracardiac electrograms (EGMs) in sinus rhythm (SR), at the onset of spontaneous ventricular tachyarrhythmias (VT) or during their course. This allows the investigation of unknown features of the heart electrical activity associated with different cardiac rhythms. In this study we propose a non conventional cardiac electrical activity characterization (CEAC) that extracts quantitative information about the power spectrum wideness and variability of the beat-by-beat morphology. We analyze 293 EGMs from 40 patients who underwent implantation of St Jude Medical-Ventritex ICDs that allow the storage of EGMs with two different modes of recording: bipolar (BIP) and unipolar or far-field (FF). The EGMs are studied with this CEAC by (1) exploring differences between the CEAC measured from FF and BIP EGMs during similar cardiac rhythms, and (2) investigating the mode of recording that allows a better separation between SR and VT rhythms. Results show that, with similar cardiac rhythm, the CEACs from FF or BIP recordings are different (for SR rhythm: sensitivity 81.5%, specificity 93.6%; for VT rhythm: sensitivity and specificity 100%); thus FF and BIP EGMs analyze different aspects of cardiac activity. The CEAC applied to FF EGMs distinguishes better EGMs obtained during SR from VT rhythms (VT vs SR with sensitivity 92.7% and specificity 79.7%) than when it is applied to BIP signals (VT vs SR with sensitivity 60% and specificity 73.3%).

Acute comparative effect of right and left ventricular pacing in patients with permanent atrial fibrillation.

We tested the hypothesis that left ventricular (LV) pacing is superior to right ventricular (RV) apical pacing in patients undergoing atrioventricular (AV) junction ablation and pacing for permanent atrial fibrillation. The potential benefit of LV over RV pacing needs to be evaluated without the confounding effect of other variables that can influence cardiac performance. An acute intrapatient comparison of the QRS width and echocardiographic parameters between RV versus LV pacing was performed within 24 h after ablation in 44 patients. Both modes of pacing were also compared with pre-implantation values. Compared with RV pacing, LV pacing caused a 5.7% increase in the ejection fraction (EF) and a 16.7% decrease in the mitral regurgitation (MR) score; the QRS width was 4.8% shorter with LV pacing. Similar results were observed in patients with or without systolic dysfunction and/or native left bundle branch block, except for a greater improvement in MR in the latter group. Compared with pre-ablation measures, the EF increased by 11.2% and 17.6% with RV and LV pacing, respectively; the MR score decreased by 0% and 16.7%; and the diastolic filling time increased by 12.7% and 15.6%.Rhythm regularization achieved with AV junction ablation improved EF with both RV and LV pacing; LV pacing provided an additional modest but favorable hemodynamic effect, as reflected by a further increase of EF and reduction of MR. The effect seems to be equal in patients with both depressed and preserved systolic functions and in those with and without native left bundle branch block.

Combined use of morphology discrimination, sudden onset, and stability as discriminating algorithms in single chamber cardioverter defibrillators.

Morphology Discrimination (MD) is a rhythm discriminator based on QRS morphology analysis that can be combined with other discriminators like Stability, with or without Sinus Interval History (SIH) and Sudden Onset. Thirty-five patients implanted with a St. Jude Medical single chamber ICD were evaluated during exercise testing, during induced AF, and during follow-up for 14 +/- 5 months. At exercise testing (60 episodes detected) MD had a specificity (SP) of 96.7% and Sudden Onset a SP of 91.7%; during induced AF (25 episodes) both MD and Stability had a SP of 96.0%. The diagnostic performance on spontaneous arrhythmias was as follows: for ventricular tachycardia (126 episodes) a sensitivity (SE) of 94.4% for MD, 92.1% for Sudden Onset, 89.7% for Stability without SIH and 79.4% for Stability + SIH; for sinus tachycardia (44 episodes) a SP of 86.4% for MD, 97.7% for Sudden Onset, 2.3% for Stability and of 95.5% for Stability + SIH. For AF (165 cases) a SP of 67.9% for MD, 69.1% for Stability and 90.3% for Stability + SIH, 44.8% for Sudden Onset. Use of MD alone provided a SE of 94.4% and a SP of 71.4% for spontaneous arrhythmias and combined use of the discriminators in a "2 of 3" diagnostic logic implied a SP of 90.9% with maintenance of 96.0% of SE. In single chamber ICDs a wide range of SE/SP ratios may be obtained by use of multiple discriminators, but use of the algorithm in a 2 of 3 diagnostic logic may achieve a SP of 90.9% and a SE of 96.0%.